Volume 36, No 3, Mar 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 3, March 2026: 181-196

ORIGINAL ARTICLES

R-loops orchestrate RNAPII transcriptional reprogramming for the maternal-to-zygotic transition

Yaoyi Li^1,2,† , Qing Li^3,4,† , Xinxiu Wang^3,4,† , Chao Di² , Yingliang Sheng^2,3 , Ying Ma² , Junzhi Liao^1,2,3 , Qingqing Cai³ , Sainan Huang^2,3 , Jiayu Chen⁵ , Guangming Wu² , Lingling Zhang⁶ , Guangjin Pan³ , Shaorong Gao⁵ , Hongjie Yao^1,2,*

¹State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
²Department of Basic Research, Guangzhou National Laboratory, Guangzhou, Guangdong, China
³Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
⁴University of Chinese Academy of Sciences, Beijing, China
⁵School of Life Sciences and Technology, Tongji University, Shanghai, China
⁶Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
^†These authors contributed equally: Yaoyi Li, Qing Li, Xinxiu Wang
Correspondence: Hongjie Yao(yao_hongjie@gzlab.ac.cn)

R-loops are pervasive genomic structures that link epigenetic modification and transcriptional regulation. However, the functional roles and regulatory mechanisms of R-loops during preimplantation development in mammals remain unexplored. Here, we reveal that the reprogramming of R-loops across developmental stages depends on CG density, with CG-poor R-loops more stage specific and strongly associated with early embryonic development. Loss of CG-poor R-loops causes severe defects in the maternal-to-zygotic transition (MZT) and preimplantation embryo development. This abnormal maintenance of CG-poor R-loops promotes premature activation of major zygotic genome activation (ZGA) genes. CG-poor R-loops inhibit DDX21 helicase activity on the 7SK/HEXIM1 snRNP complex, restricting CDK9 release and subsequent phosphorylation of Ser2 at the C-terminal domain of RNA polymerase II (RNAPII S2p) — the biochemical hallmark of pause release — thus enforcing RNAPII accumulation at major ZGA gene promoters to ensure productive transcription. These findings establish R-loops as direct modulators of RNAPII pause release, promoting the temporal fidelity of gene expression during the MZT.

https://doi.org/10.1038/s41422-025-01208-2

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